INTRODUCTION TO PLASMA CELL DISORDERS
Plasma cell disorders encompass a group of hematologic malignancies characterized by neoplastic clonal proliferation of plasma cells producing a monoclonal protein. The range and severity of diseases are broad and include multiple myeloma (MM), monoclonal gammopathy of undetermined significance (MGUS), Waldenström macroglobulinemia (WM), and amyloidosis. The monoclonal protein (M protein) varies by disease entity; MM generally produces IgG and IgA, whereas WM is caused by IgM gammopathy.
MULTIPLE MYELOMA
GENERAL PRINCIPLES
Multiple myeloma (MM) results when there is neoplastic clonal proliferation of plasma cells resulting in production of a monoclonal immunoglobulin (Ig), also known as the M protein, which is present in the blood and/or urine. Lytic bone lesions in MM result from disruption of the normal bone remodeling process, caused by upregulation of osteoclasts, inhibition of osteoblasts, and interactions with bone marrow stromal cells. Even with adequate therapy, the lytic lesions remain, and new bone formation does not occur.
Epidemiology
In the United States, ~5.6 of 100,000 people are diagnosed with MM each year. In 2010, 20,180 new cases were diagnosed and 10,650 deaths occurred.
DIAGNOSIS
Clinical Presentation
Presentation of MM can be nonspecific, including complaints of fatigue, bone pain, weight loss, parasthesias/neuropathy, and recurrent bacterial infections. The hallmark of the disease is bone destruction, and 85% of patients have lytic lesions or diffuse osteopenia at diagnosis. Approximately 60% of patients develop pathologic fractures and 66% have symptomatic bone pain. MM can be associated with plasmacytomas that invade vertebrae which may result in vertebral fracture or neurologic emergencies such as cord compression.
Diagnostic Criteria
The International Myeloma Working Group and Mayo Clinic developed diagnostic criteria for MM, refined in 2003. All three criteria must be met:
Presence of a serum and/or urine monoclonal protein (except in patients with true nonsecretory MM)
Presence of clonal bone marrow plasma cells ≥10%
Presence of end-organ damage attributed to the plasma cell disorder such as hypercalcemia; renal insufficiency; normochromic/normocytic anemia; or bone lesions (lytic lesions, osteopenia, or fracture)
A diagnosis of smoldering MM (SMM), sometimes called asymptomatic MM, is made by meeting both of the following criteria:
Serum monoclonal protein ≥3 g/dL and/or clonal bone marrow plasma cells ≥10%
Absence of end-organ damage attributed to the plasma cell disorder
Smoldering MM progresses to MM at a rate of approximately 10% per year1.
Diagnostic Testing
Laboratories
All patients suspected of having MM should undergo an extensive workup. Initial laboratories should include CBC, electrolytes, BUN, creatinine, and calcium. Examination of the peripheral blood smear may reveal presence of rouleaux formation. A serum protein electrophoresis (SPEP) with immunofixation, quantitative immunoglobulins, and measurement of serum-free light chains should be performed. Once the diagnosis of a plasma cell disorder is established, 24-hour urine, urine protein electrophoresis (UPEP) and immunofixation are needed. LDH can be measured to reflect tumor burden, while serum β2 -microglobulin and albumin serve as important prognostic indicators. An M protein is detectable in the serum of ~90% of patients with MM, with 50% of patients having IgG and 20% having IgA. Sixteen percent of patients secrete light chains only.
Imaging
A skeletal survey to assess for lytic lesions should be performed. CT/MRI can be considered in patients with bone pain not explained by skeletal survey to assess for occult fracture.
Diagnostic Procedures
A bone marrow aspirate and biopsy should be done with immunophenotyping, cytogenetics, and fluorescence in situ hybridization (FISH), as certain translocations have prognostic significance.
TREATMENT
The decision of when to treat typically depends on presence of symptoms from the disease. A Cochrane review compared chemotherapy at the time of diagnosis to chemotherapy at the time of disease progression and found that early treatment effectively delayed progression of the disease; however, there were no significant effects on mortality or on response rate to initial therapy.2 Patients with SMM may remain stable for years before requiring therapy, and should be followed every 3 months to monitor for disease progression.
Initial therapy. Patients with symptomatic disease on presentation should undergo treatment as survival without therapy is a median of 6 months. The goalsof induction therapy include decreasing tumor burden and symptoms, improving end-organ damage, and prolonging survival. The preferred induction regimen has not been clearly defined, and the upfront therapy of myeloma is rapidly evolving. 3,4Melphalan and prednisone (MP) is a well tolerated regimen with a response rate that approaches 50%. However, in those who are expected to proceed to stem cell transplantation (SCT), MP should be avoided because the alkylating agent compromises stem cell reserve. Thalidomide/dexamethasone (TD) was commonly used in the recent past, but recent studies have demonstrated superiority of alternate regimens. Lenalidomide/dexamethasone (LD) has shown superiority over TD, with increased partial response rate (PR) of 80% versus 61%, in addition to increasing time to progression (TTP), progression-free survival (PFS), and overall survival (OS).5 The toxicity profile for thalidomide includes venous thromboembolism (VTE) and peripheral neuropathy, while that for lenalidomide includes myelotoxicity and VTE. Bortezomib, a proteasome inhibitor, has high activity in MM, and, in combination with dexamethasone, it has an overall response of 65% in untreated patients.6 Toxicity profile for bortezomib includes peripheral neuropathy. An older regimen consisting of vincristine, doxorubicin, and dexamethasone (VAD) has comparable RR to newer therapy; however, its use has fallen out of favor due to a cumbersome administration schedule and requirement for central line. Combination therapies that incorporate lenalidomide, bortezomib, steroids, and alkylators, as well as various consolidation and maintenance approaches, are under active investigation.
Hematopoetic stem cell transplant. Autologous SCT has been shown to extend disease-free survival in patients with myeloma; although its role may evolve given improvements in induction therapy. Currently, most patients deemed suitable for autologous SCT proceed to harvesting of stem cells after several cycles of induction therapy. Response rates to SCT approach 90%, with one-third of patients experiencing a complete response. The main deciding factors for who is eligible to undergo autologous SCT include age, performance status, and presence of comorbidities. Allogeneic transplants are also occasionally performed, although they are generally reserved for young patients with a matched sibling donor who have failed autologous SCT. Initial response to induction therapy has not been shown to predict outcome after autologous SCT. Maintenance therapy with lenalidomide or other active agents may extend disease-free survival post-SCT.
Adjunctive therapy. Given advancements in overall survival of MM, the role of adjunctive therapy is increasing. Bisphosphonates play a role in decreasing skeletal events (i.e., fractures, lytic lesions, and osteoporosis) and in decreasing bone pain due to lytic lesions. Radiation therapy is effective in decreasing bony pain from distinct lesions and can be used during complications such as spinal cord compression. Patients on thalidomide or lenalidomide should be on prophylactic anticoagulation because of increased risk of thrombotic events.
FOLLOW-UP
Follow-up of MM should be done by following the M-protein level and other markers of disease progression including serum-free light chains, CBC, and serum creatinine. Skeletal surveys are not used to follow disease response as lesions may not show healing on x-rays.
PROGNOSIS
International Staging System (ISS). The ISS was developed in 2005 and is based on a database of more than 10,000 patients. The staging system also serves as an important prognostic tool. Median survivals are 62, 44, and 29 months for stages I, II, and III, respectively.7
Stage I: β2-Microglobulin <3.5 mg/L and serum albumin ≥3.5 g/dL
Stage II: Neither stage I nor stage III
Stage III: β2-Microglobulin ≥ 5.5 mg/L
Durie–Salmon staging system. The older staging system is called the Durie–Salmon criteria published in 1975, also consist of three stages. This system was developed based on total tumor cell mass but has not been shown to correlate with prognosis. A designation of A or B was added to the clinical stage for patients with or without a serum creatinine ≥2 mg/dL, respectively.
Stage I: All of the following: hemoglobin >10 g/dL, normal serum calcium, normal skeletal survey or a solitary plasmacytoma, serum IgG <5 g/dL and IgA <3 g/dL and urine light chain excretion <4 g/24 h.
Stage II: Neither stage I nor stage III.
Stage III: One or more: hemoglobin <8.5 g/dL, serum calcium >12 mg/dL, ≥3 lytic bone lesions, serum IgG >7 g/dL or IgA >5 g/dL, and urine light chain excretion >12 g/24 h.
Cytogenetics. While utilization of this information has yet to lead to alterations in clinical management, identification of certain cytogenetic abnormalities can aid in prognostication.
Cytogenetics: Poor prognosis with deletion of chromosome 13 or hypodiploidy.
FISH: Poor prognosis with t(4;14), t(14;16), 13q-, and 17p-.
SOLITARY PLASMACYTOMAS
GENERAL PRINCIPLES
Solitary plasmacytoma is a collection of monoclonal plasma cells localized in tissue without evidence of a systemic plasma cell dyscrasia. There are two types of solitary plasmacytomas; solitary plasmacytoma of bone (SBP) and solitary extramedullary plasmacytoma (SEP). Plasmacytomas in the bone are more common than in extra-medullary sites, with both constituting less than 10% of all plasma cell dyscrasias.
Epidemiology
The incidence of solitary plasmacytoma occurs at an annual rate of approximately 0.34 per 100,000 person-years in the United States. The average age of diagnosis is 55 years, with incidence for both higher in males than in females.
DIAGNOSIS
Clinical Presentation
Solitary plasmacytomas of bone often present with bony pain, pathological fracture, or cord compression. Bones undergoing increased hematopoiesis are more commonlyinvolved in SBP, with the three most common involved sites including vertebrae, pelvis, and upper extremities. While SEP has a predilection for the aerodigestive tract, the most common location tends to be in the head and neck area.
Diagnostic Criteria
Diagnostic criteria for solitary plasmacytoma must encompass each of the following:
presence of biopsy proven plasmacytoma showing a population of clonal plasma cells;
absence of clonal plasma cell population on bone marrow biopsy and aspiration;
absence of end-organ damage that can be attributed to an underlying plasma cell disorder such as hypercalcemia; renal insufficiency; or anemia; and
absence of other lytic lesions on skeletal survey or MRI of the spine/pelvis.
Diagnostic Testing
Laboratories
Diagnostic testing for solitary plasmacytoma should contain tests to exclude alternate diagnoses. Initial laboratory workup includes CBC, electrolytes, BUN, creatinine, and calcium. An SPEP and UPEP with immunofixation should be performed as up to 74% of cases may have presence of a small M protein. The presence of M protein tends to be higher in patients with SBP as oppose to SEP.8 Serum free light chains as well as immunoglobulin levels should also be done.
Imaging
Askeletal survey should be done to exclude presence of multiple lytic lesions. Also, MRI of the spine and pelvi s should be performed to exclude lesions that may have been missed on x-ray.
Diagnostic Procedures
Biopsy of the suspected solitary lesion should be performed at the onset of work up to establish the working diagnosis. To exclude a significant population of clonal plasma cells in the bone marrow, a bone marrow biopsy and aspiration should be performed.
TREATMENT
The mainstay of therapy for solitary plasmacytoma is localized radiation therapy at a dose of 40 to 50 Gy over 20 to 25 treatments from which response exceeds 90%.9 Surgery is an alternative if immediate tumor debulking is needed for complications such as fracture or spinal cord compression; with adjuvant radiation therapy considered. There is controversial data on the use of adjuvant chemotherapy, mainly with melphalan and prednisone.
PROGNOSIS
More than 50% of patients with SBP will progress to MM, compared to fewer than 30% with SEP, with median time to progression of 2 to 4 years. Recently, two prognostic indicators have been identified to predict who will develop MM. A study atMayo Clinic identified that patients with SBP who have an abnormal serum-free light chain (FLC) ratio or presence of a urinary M protein at diagnosis have higher risk of progression at 5 years (44% vs. 25%).10 Patients whose serum M protein is still elevated 1 year after treatment also have an increased risk of progression. Overall survival is higher in SEP than SBP (10 year survival 70% vs. 50%).
MONOCLONAL GAMMOPATHY OF UNDETERMINED SIGNIFICANCE
GENERAL PRINCIPLES
Monoclonal gammopathy of undetermined significance (MGUS) is a clinically asymptomatic, premalignant condition characterized by the presence of a small neo-plastic clonal population of plasma cells in the bone marrow. The pathophysiology of the clonal population is the same as in MM; however, definitive criteria of MGUS are the absence of end organ damage caused by the clonal population. It is estimated that the prevalence of MGUS is approximately 3.2% in Caucasian patients over the age of 50 and reaching 7.5% in those patients of age ≥85.11
DIAGNOSIS
Clinical Presentation
Patients with MGUS are clinically asymptomatic. It is typically diagnosed during routine workup of elevated total serum protein or proteinuria.
Diagnostic Criteria
The International Myeloma Working Group developed diagnostic criteria for MGUS in 2003. All three criteria must be met:
presence of a serum monoclonal protein (M protein) IgA, IgG, or IgM <3 g/dL;
presence of fever that 10% clonal bone marrow plasma cells; and
absence of end-organ damage attributed to the underlying plasma cell disorder such as hypercalcemia; renal insufficiency; normochromic normocytic anemia; or lytic bone lesions.
Diagnostic Testing
Laboratories
All patients should undergo similar testing as with a workup for MM. Initial laboratory workup should include a CBC, serum electrolytes, BUN, serum creatinine, and serum calcium. A serum and urine protein electrophoresis (SPEP) with immunofixation, quantitative immunoglobulins, and measurement of serum free light chains should be performed.
Imaging
A skeletal survey to assess for lytic lesions should be performed on all patients.
Diagnostic Procedures
A bone marrow aspirate and biopsy should be done with immunophenotyping, cytogenetics, and fluorescence in situ hybridization (FISH).
TREATMENT
There is currently no treatment indicated for MGUS. As it is generally a slowly progressing disorder, the majority of patients will not progress to a malignant disease. Generally, it is accepted practice to follow these patients annually with evaluation including SPEP, UPEP, CBC, and creatinine. If patients develop symptoms concerning for progression to myeloma, they should undergo more extensive evaluation.
PROGNOSIS
In general, the rate of progression for all patients diagnosed with MGUS is approximately 1% per year. However, prognostic indicators have recently been defined that indicate patients at higher risk of progression (Table 13-1).12
WALDENSTRÖM MACROGLOBULINEMIA
GENERAL PRINCIPLES
Waldenström macroglobulinemia (WM), also known as lymphoplasmacytic lymphoma, is a rare malignant lymphoproliferative disorder characterized by the production of an IgM paraprotein. It differs from IgM MM in that it is characterized by the presence of excess lymphoplasmacytoid cells in the bone marrow.
Epidemiology
There are approximately 1500 new cases of WM annually in the United States. The rate is higher in men than women, and higher in Caucasians than African Amerians.
DIAGNOSIS
Clinical Presentation
Presentation of WM is generally vague and can be attributed to infiltration of lymphocytes or plasmacytoid cells into tissue and organs, secondary to the monoclonal IgM protein, or paraneoplastic neuropathy. Infiltration into organs can lead tohepatosplenomegaly, lymphadenopathy, or dermatologic findings. At high quantities, the IgM protein can lead to hyperviscosity of the blood causing signs of stasis including stroke, transient ischemic attacks, and venous thromboembolism. There is a correlation between hepatitis C and increased incidence of WM, and 10% of patients with WM will have cryoglobulinemia.
Diagnostic Criteria
Two diagnostic criteria must be fulfilled to establish a diagnosis of WM:
IgM monoclonal protein of any value in the serum
≥10% lymphocytes with plasmacytoid differentiation in the bone marrow in an intertrabecular pattern
Diagnostic Testing
Diagnostic testing should include SPEP and UPEP with immunofixation and bone marrow biopsy with aspiration to establish the diagnosis. Ancillary testing should include CBC, LDH, β2-microglobulin, and serum viscosity.
TREATMENT
Treatment of WM should only be initiated when symptoms develop or there is evidence of significant end organ damage.13 Those without these findings are termed to have smoldering WM. While there is no set standard of therapy, treatment generally includes alkylating agents, nucleoside analogues, and rituximab. Patients with symptoms of hyperviscosity should be treated with emergent plasmapheresis to decrease the burden of the IgM monoclonal protein. In qualifying patients with refractory or relapsed disease, high dose chemotherapy followed by autologous HCT should be offered. No treatment has been shown to cure, with median survival from time of diagnosi ~5 years.
AMYLOIDOSIS
GENERAL PRINCIPLES
Amyloidosis is characterized by the tissue deposition of amyloid fibrils in a betapleated sheet configuration which is resistant to proteolysis.
Epidemiology
It is a rare disorder, affecting 5.1 to 12.8 per million people each year.
DIAGNOSIS
Clinical Presentation
Clinical presentation of amyloid is heterogeneous and depends on type of amyloid. The majority of symptoms are defined by the predominant organ affected and can include nephrotic syndrome, cardiomyopathy, neuropathy, hepatic dysfunction, and bleeding diatheses. Specific physical exam findings may include hepatomegaly, periorbital ecchymoses, macroglossia, and edema.
Diagnostic Criteria
Diagnostic criteria depend on the type of amyloid being diagnosed.
Primary amyloid (AL amyloid) is a plasma cell dyscrasia in which monoclonal Ig light chain fragments lead to deposition of protein. As such, a majority of patients will have a monoclonal light chain detected in the serum or urine. It can occur alone or in conjunction with another plasma cell dyscrasia.
Secondary amyloid (AA amyloid) occurs in conjunction with chronic diseases such as rheumatoid arthritis (RA), in which the chronic inflammatory state of the disease leads to deposition of acute phase reactant serum amyloid A. Senile systemic amyloid has a predilection to affect the heart and is due to deposition of transthyretin. Dialysis associated amyloid occurs in patients on long term hemodialysis and is the result of β2-microglobulin fibril deposition. There are numerous other heritable forms of amyloidosis.
Diagnostic Testing
Regardless of the type of amyloid, tissue biopsy is required to establish the diagnosis. In general, biopsy should be derived from the organ most affected. However, if this is unattainable, abdominal fat pad aspiration is recommended. Presence of amyloid is revealed with use of Congo red staining which shows a characteristic apple green birefringent appearance on polarized microscopy.
When AL amyloid is suspected in a patient without underlying known plasma cell dyscrasias, SPEP and UPEP with immunofixation should be performed. Bone marrow biopsy and aspiration can confirm presence of a plasma cell dyscrasia. Serum-free light chains may also be useful in diagnosis.
Ancillary testing as needed should be performed to determine the extent of end organ damage.
TREATMENT
Treatment varies with the type of amyloid. If amyloid is felt to be secondary to a plasma cell dyscrasia or another chronic medical condition, then treatment of the underlying disorder is required. Treatment of a hereditary amyloidosis may require organ transplantation in those who are candidates. Overall, prognosis in those with amyloid is poor and novel treatments continue to be investigated.
REFERENCES
1. Kyle RA, Remstein ED, Therneau TM, et al. Clinical course and prognosis of smoldering (asymptomatic) multiple myeloma. N Engl J Med. 2007;356:2582–2590.
2. He Y, Wheatley K, Glasmacher A, et al. Early versus deferred treatment for early stage multiple myeloma. Cochrane Database Syst Rev. 2003;1:CD004023.
3. Morabito F, Gentile M, Mazzone C, et al. Therapeutic approaches for newly diagnosed multiple myeloma patients in the era of novel drugs. Eur J Haematol. 2010;85:181–191.
4. Engelhardt M, Kleber M, Udi J, et al. Consensus statement from European experts on the diagnosis, management, and treatment of multiple myeloma: from standard therapy to novel approaches. Leuk Lymphoma.2010;51:1424–1443.
5. Gay F, Hayman SR, Lacy MQ, et al. Lenalidomide plus dexamethasone versus thalidomide plus dexamethasone in newly diagnosed multiple myeloma: a comparative analysis of 411 patients. Blood.2010;115:1343–1350.
6. Rosinol L, Oriol A, Mateos MV, et al. Phase II PETHEMA trial of alternating bortezomib and dexamethasone as induction regimen before autologous stem-cell transplantation in younger patients with multiple myeloma: efficacy and clinical implications of tumor response kinetics. J Clin Oncol. 2007;25:4452–4458.
7. Greipp PR, San Miguel J, Durie BG, et al. International staging system for multiple myeloma. J Clin Oncol. 2005;23:3412–3420.
8. Dimopoulos MA, Moulopoulos LA, Maniatis A, et al. Solitary plasmacytoma of bone and asymptomatic multiple myeloma. Blood. 2000;96:2037–2044.
9. Soutar R, Lucraft H, Jackson G, et al. Guidelines on the diagnosis and management of solitary plasmacytoma of bone and solitary extramedullary plasmacytoma. Br J Haematol. 2004;124:717.
10. Dingli D, Kyle RA, Rajkumar SV, et al. Immunoglobulin free light chains and solitary plasmacytoma of bone. Blood. 2006;108:1979.
11. Kyle RA, Therneau TM, Rajkumar SV, et al. Prevalence of monoclonal gammopathy of undetermined significance. N Engl J Med. 2006;354:1362–1369.
12. Rajkumar SV, Kyle RA, Therneau TM, et al. Serum free light chain ratio is an independent risk factor for progression in monoclonal gammopathy of undetermined significance. Blood. 2005;106:812–818.
13. Ansell SM, Kyle RA, Reeder CB, et al. Diagnosis and management of Waldenström macroglobulinemia: Mayo stratification of macroglobulinemia and risk-adapted therapy (mSMART) guidelines. Mayo Clin Proc.2010;85:824–833.